1. Field of the Invention
The present invention relates to methods for preventing cell death, and to methods of treating conditions that require prevention, inhibition, and/or amelioration of cell death and tissue necrosis. The invention encompasses administering a segment of neural thread proteins (NTP), or a homologue, derivative, variant or mimetic thereof, to a mammal experiencing cell death. The segment can be administered intramuscularly, orally, intravenously, intraperitoneally, intracerebrally (intraparenchymally), intracerebroventricularly, intratumorally, intralesionally, intradermally, intrathecally, intranasally, intraocularly, intraarterially, topically, transdermally, via an aerosol, infusion, bolus injection, implantation device, sustained release system etc., either alone or conjugated to a carrier. Alternatively, the segment can be expressed in vivo by administering a gene that expresses the segment, by administering a vaccine that induces such production or by introducing cells, bacteria or viruses that express the segment in vivo, either because of genetic modification or otherwise.
2. Description of Related Art
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive impairments in memory, behavior, language, and visuo-spatial skills, ending ultimately in death. Hallmark pathologies within vulnerable regions include extracellular β-amyloid deposits, intracellular neurofibrillary tangles, synaptic loss, and extensive neuronal cell death. Research on the causes and treatments of Alzheimer's disease has led investigators down numerous avenues. Considerable evidence has implicated alterations in production or processing of the human amyloid precursor protein (APP) in the etiology of the disease. However, intensive research has proven that AD is a multifactorial disease with many different, perhaps overlapping, etiologies.
Because of this, those in the field have conducted significant research and clinical investigations to study the structural deficiencies, chemical changes, and functional abnormalities both within the brain and within different populations of nerve cells. The depth of such investigations and studies are represented by the following publications, which represent only a handful of the vast reports in this arena: Neurobiology of Alzheimer's Disease (D. Dawbarn and S. J. Allen, Editors), Bios, Oxford 1995; Dementia, (J. Whitehouse, Ed.), F. A. Davis Company, Philadelphia, 1993; Alzheimer's Disease: Senile Dementia and Related Disorders (Katzman, R, and R. L. Bick, Eds), Raven Press, New York, 1994, pages 47-51; Alzheimer's Disease and Related Disorders, Etiology, Pathogenesis and Therapeutics (Iqbol, K., et al., Eds.), Wiley, Chichester, 1999; Alzheimer's Disease: Advances in Clinical and Basic Research (Corain, B, Ed.), Wiley, New York, 1993; Alzheimer's Disease: Clinical and Treatment Perspectives (Cutler, N. R., et al., Eds.), Wiley, Chichester, 1995; Alzheimer's Disease: Therapeutic Strategies (Giacobini, E., Becker, R., Eds.), Birkhauser, Boston, 1994; Paykel, et al., Arch. Gen. Psychiat., 51:325-332 (1994); Amaducci, et al., Neurology, 36:922-931 (1986); McKhann, et al., Neurology 34:939-944 (1984), Heston et al., Arch. Gen. Psychiatry 38:1085-1090 (1981); Aging of the Brain (Gispen and Traber, editors), Elsevier Science Publishers, Amsterdam, 1983, pages 275-282; Heyman et al., Ann. Neurol 15:335-341 (1984); Brayne C. and P. Calloway, Lancet 1:1265-1267 (1988); Roth et al., Br. J. Psychiatry 149:698-709 (1986); Medical Research Council, Report from the NRC Alzheimer's Disease Workshop, London, England, 1987; Morris et al., Neurology 41:469-478 (1991); and the references cited within each of these publications.
To date, Alzheimer's disease is the third most expensive disease in the United States, costing society approximately $100 billion each year. It is one of the most prevalent illnesses in the elderly population, and with the aging of society, will become even more significant. Costs associated with AD include direct medical costs such as nursing home care, direct non-medical costs such as in-home day care, and indirect costs such as lost patient and care giver productivity. Medical treatment and behavior modification may have economic benefits by slowing the rate of cognitive decline, delaying institutionalization, reducing care giver hours, and improving quality of life. Pharmacoeconomic evaluations have shown positive results regarding the effect of drug therapy and behavior modification on nursing home placement, cognition, and care giver time.
Neural thread proteins (NTP) are a family of recently characterized brain proteins. One member of this family, AD7C-NTP, is a ˜41 kD membrane associated phosphoprotein with functions related to neuritic sprouting (de la Monte et al., J. Clin. Invest., 100:3093-3104 (1997); de la Monte et al., Alz. Rep., 2:327-332 (1999); de la Monte SM and Wands JR, Journal of Alzheimer's Disease, 3:345-353 (2001)). The gene that encodes AD7C-NTP and predicted protein sequence for AD7C-NTP has been identified and described (de la Monte et al., J. Clin. Invest., 100:3093-3104 (1997)). In addition to the ˜41 kD species, other species of neural thread protein (˜26 kD, ˜21 kD, ˜17 kD, and ˜15 kD) have been identified and associated with neuroectodermal tumors, astrocytomas, and glioblastomas and with injury due to hypoxia, schema, or cerebral infarction (Xu et al., Cancer Research, 53:3823-3829 (1993); de la Monte et al., J. Neuropathol. Exp. Neurol., 55(10):1038-50 (1996), de la Monte et al., J. Neurol. Sci., 138(1-2):26-35 (1996); de la Monte et al., J. Neurol. Sci., 135(2):118-25 (1996); de la Monte et al., J. Clin. Invest., 100:3093-3104 (1997); and de la Monte et al., Alz. Rep., 2:327-332 (1999)).
Species of neural thread protein have been described and claimed in U.S. Pat. Nos. 5,948,634; 5,948,888; and 5,830,670, all for “Neural Thread Protein Gene Expression and Detection of Alzheimer's Disease” and in U.S. Pat. No. 6,071,705 for “Method of Detecting Neurological Disease or Dysfunction.” The disclosures of these patents are specifically incorporated herein by reference in their entirety. As described therein, NTP is upregulated and produced during cell death. Thus, dead and dying nerve cells are described as overproducing NTP, and accordingly, its presence indicates the death of nerve cells and the onset of Alzheimer's disease (AD).
Other species of neural thread protein have been identified as other products of the AD7c-NTP gene (e.g. a 112 amino acid protein described in NCBI Entrez-Protein database Accession #XP—032307 PID g15928971) or as being similar to neural thread proteins (e.g. a 106 amino acid protein described in NCBI Entrez-Protein database Accession #AAH14951 PID g15928971, another 106 amino acid protein described in NCBI Entrez-Protein database Accession #XP—039102 PID g18599339 and a 61 amino acid protein described in NCBI Entrez-Protein database Accession #AAH02534 PID g12803421).
There is compelling evidence linking the AD7C-NTP specie of neural thread protein in particular with AD and its upregulation during cell death in AD. AD7C-NTP mRNA is upregulated in AD brain compared to controls; AD7C-NTP protein levels in brain and in CSF are higher in AD than controls; and AD7C-NTP immunoreactivity is found in senile plaques, in neurofibrillary tangles (NFT), in degenerating neurons, neuropil threads, and dystrophic neurotic sprouts in AD and Down syndrome brains (Ozturk et al., Proc. Natl. Acad. Sci. USA, 86:419-423 (1989); de la Monte et al., J. Clin. Invest., 86(3):1004-13 (1990); de la Monte et al., J. Neurol. Sci., 113(2): 152-64 (1992); de la Monte et al., Ann. Neurol., 32(6):733-42 (1992); de la Monte et al., J. Neuropathol. Exp. Neurol., 55(10): 1038-50 (1996), de la Monte et al., J. Neurol. Sci., 138(1-2):26-35 (1996); de la Monte et al., J. Neurol. Sci., 135(2):118-25 (1996); de la Monte et al., J. Clin. Invest., 100:3093-3104 (1997); and de la Monte et al., Alz. Rep., 2:327-332 (1999)). Immunocytochemistry demonstrated that the AD7C-NTP protein is localized within cells, within fine processes within the neuropil, or is extracellular in both AD and Down's Syndrome brains. de la Monte et al., Ann. Neurol., 32(6):733-42 (1992). Two types of cells contain AD7C-NTP: neurons and astrocytes (Id.). The affected neurons are the large pyramidal type that typically contain the neurofibrillary tangles well known in AD brain (Id.).
Elevated levels of AD7C-NTP protein have been found in both CSF and urine of AD patients, showing its accuracy as a biochemical marker for this devastating illness (de la Monte and Wands, Front Biosci 7: 989-96 (2002); de la Monte and Wands, Journal of Alzheimer's Disease 3: 345-353 (2001); Munzar et al, Alzheimer's Reports 4: 61-65 (2001); Kahle et al, Neurology 54: 1498-1504 (2000) and Averback Neurology 55: 1068 (2000); Munzar et al, Alzheimer Reports 3: 155-159 (2000); de la Monte et al, Alzheimer's Reports 2: 327-332 (1999); Ghanbari et al, J Clin Lab Anal 12: 285-288 (1998); Ghanbari et al, J Clin Lab Anal 12: 223-226 (1998); Ghanbari et al, Journal of Contemporary Neurology 1998; 4A: 2-6 (1998); and de la Monte et al, J Clin Invest 100: 3093-3104 (1997).
Over-expression of the AD7C-NTP gene also has been linked to the process of cell death in Alzheimer's disease (de la Monte and Wands, J. Neuropatho. and Exp. Neuro., 60:195-207 (2001); de la Monte and Wands, Cell Mol Life Sci 58: 844-49 (2001). AD7C-NTP has also been identified in Down's Syndrome brain tissue (Wands et al., International Patent Publication No. WO 90/06993; de la Monte et al, J Neurol Sci 135: 118-25 (1996); de la Monte et al., Alz. Rep., 2:327-332 (1999)). There is some evidence that over-expression of the AD7C-NTP gene also may be associated with normal tension glaucoma (Golubnitschaja-Labudova et al, Curr Eye Res 21: 867-76 (2000)).
The present inventor recently discovered that released AD7C-NTP protein was cytotoxic and capable of causing cell death to other cells in tissue (as compared with up-regulated AD7C -NTP produced by the dying cell itself), as disclosed in pending U.S. patent application Ser. No. 10/092,934 and entitled “Method of Using Neural Thread Proteins to Treat Tumors and other Conditions Requiring the Removal or Destruction of Cells,” the disclosure of which is incorporated by reference herein in its entirety. Accordingly, it would be desirable to prevent, inhibit, modulate or ameliorate cell death and tissue necrosis associated with neural thread proteins, especially in AD brain.
It has also recently been discovered that segments of NTP could be used in binding assays, purification of NTP, and as diagnostics as a substitute for NTP, as disclosed in pending U.S. patent application Ser. No. 09/697,590, now U.S. Pat. No. 7,259,232, and entitled: “Preferred Segments of Neural Thread Protein,” the disclosure of which is incorporated by reference herein in its entirety.
Throughout this description, including the foregoing description of related art, any and all publicly available documents described herein, including any and all U.S. patents, are specifically incorporated by reference herein in their entirety. The foregoing description of related art is not intended in any way as an admission that any of the documents described therein, including pending United States patent applications, are prior art to the present invention.